Amorphous substance of tricyclic triazolobenzazepine derivative

ABSTRACT

Disclosed are 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5 H ), 10-dioxo-2 H -1,2,3-triazolo[4,5-c][1]benzazepine, which has been rendered amorphous and possesses improved absorption and dissoluvability, and a pharmaceutical composition comprising the same. Also disclosed are processes for producing 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5 H ), 10-dioxo-2 H -1,2,3-triazolo[4,5-c][1]benzazepine, which has been rendered amorphous, and a pharmaceutical composition comprising the same.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, which is in amorphousform and possesses improved dissolution and absorption, and apharmaceutical composition comprising the same.

2. Background Art

2-(1-Isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (hereinafter referred toas “compound A”) is a compound, represented by the following chemicalstructural formula, as disclosed in WO 99/16770 (Japanese Patent No.3188482 and U.S. Pat. No. 6,372,735) (the disclosure of each of thesepublications is incorporated herein by reference).

Upon oral administration, this compound exhibits a mast cell membranestabilizing action and an inhibitory activity against allergicinflammation and thus is expected to be used clinically as oralantiallergic agents. Since, however, compound A, when used in acrystalline form (hereinafter referred to as “crystalline compound A”),is poorly soluble, the compound contained in a formulation is hardlyabsorbed within the digestive tract and is less likely to be absorbed ina body. Therefore, improving solubility and bioavailability ofcrystalline compound A is required for the design and production of oralpreparations.

The present inventors have attempted various methods with a view toimproving the dissolvability of crystalline compound A. As a result, itwas found that the dissolution of crystalline compound A with the aid ofan acidic or basic additive is difficult due to the absence of afunctional group, which is dissociated or protonated in apharmaceutically acceptable pH range, in the structure of compound A.Further, even after inclusion compounds, such as cyclodextrins, orvarious surfactants, polymeric compounds or the like are added,crystalline compound A could not be substantially solubilized withoutdifficulties. Furthermore, the solubility of crystalline compound A inglycerin, propylene glycol, Macrogol 400 and the like was not on such alevel that can make crystalline compound A pharmaceutically usable. Inaddition, an experiment in which a pulverized crystal of crystallinecompound A is prepared according to the description of Japanese PatentLaid-Open No. 185013/1987 disclosing a drug, which has been renderedeasily absorbable by pulverizing was carried out. The treated drug isorally administered to experimental animals such as dogs. As a result,it was found that an improvement in absorption of preparations usingcrystalline compound A is not more than expected.

A technique known for improving the dissolution of the hardly solublecrystalline compound is to convert the crystalline compound to anamorphous compound (for example, Yu L., Advanced Drug Delivery Reviews,Vol. 48, p. 29, 2001). Specific examples thereof include heat melting,rapid crystallization by the addition of a hardly soluble solvent,lyophilization, spray drying, preparation of solid dispersion,mechanochemical conversion (such as commutation), and dehydration fromcrystalline hydrate. Most of common techniques for rendering drugsamorphous, however, could not be applied to crystalline compound A dueto the occurrence of unfavorable phenomena including that crystallinecompound A is decomposed upon heat melting due to closeness of themelting point to the decomposition point; precipitation as a crystal isobserved even by the rapid crystallization method; there is no propersolvent for lyophilization; crystalline compound A is not heat meltedeven in a thermal plastic substance and, even when dissolved in asolvent together with various additives, causes crystallization duringthe removal of the solvent by distillation under the reduced pressure(that is, a solid dispersion cannot be prepared by the melting methodand the solvent distilling-off method); pulverization or extrudertreatment does not render crystalline compound A amorphous or results inthe formation of a decomposition product; and any hydrate is not formed.

SUMMARY OF THE INVENTION

The present inventors have now found that, when compound A is dissolvedin a solvent to prepare a solution which is then spray dried, the spraydried product has significantly lowered degree of crystallization.Since, however, crystalline compound A is hardly soluble in water aswell as in various solvents, this method raised an issue about theselection of a proper solvent for spray drying. The present inventorshave found that crystalline compound A can be rendered amorphous bydissolving compound A in a certain solvent and then spray drying thesolution. They have further found that the incorporation ofmethylcellulose and/or hydroxypropylmethylcellulose can suppress thecrystallization of the amorphized compound A. The present invention hasbeen made based on such finding.

Accordingly, an object of the present invention is to provide compound Awhich has been rendered amorphous and possesses improved solubility andbioavailability, a composition comprising the same, and productionprocesses of compound A and the composition.

According to the present invention, there is provided amorphous compoundA which does not have any diffraction peak in a powder X-ray diffractionpattern and has a solubility of 15 to 20 μg/mL in a 1 wt %methylcellulose solution at 37° C.

According to the present invention, there is also provided a compositionwhich can suppress the crystallization of amorphous compound A. Thecomposition comprises the amorphous compound A according to the presentinvention and methylcellulose and/or hydroxypropylmethylcellulose.

Furthermore, according to the present invention, there is provided aprocess for producing amorphous compound A. The process comprises thesteps of: dissolving2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine in methylene chloride toprepare a solution; and then spray-drying the solution.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is powder X-ray diffraction patterns of amorphous compound A andan amorphous composition produced in Example 1 and Example 2,respectively, and crystalline compound A produced in Comparative Example1;

FIG. 2 is a diagram showing the solubility in water of amorphouscompound A produced in Example 1, amorphous compositions produced inExamples 2 and 3, and crystalline compound A produced in ComparativeExample 1;

FIG. 3 is a diagram showing the solubility of amorphous compound A in a1 wt % aqueous methylcellulose solution produced in Example 1 andcrystalline compound A produced in Comparative Example 1;

FIG. 4 is a diagram showing the solubility in water of a capsulepreparation comprising amorphous compound A produced in Example 14; and

FIG. 5 is a diagram showing a change in level of drug in plasma in anexperiment in which each of amorphous compound A produced in Example 1and crystalline compound A produced in Comparative Example 1 issuspended in a 1 wt % aqueous methylcellulose solution to preparesuspensions which are then orally administered to beagles.

DETAILED DESCRIPTION OF INVENTION

Amorphous Compound A and Production Process Thereof

Amorphous compound A according to the present invention refers to acompound in a solid state which does not have any characteristicdiffraction peak in a powder X-ray diffraction pattern. Further,amorphous compound A according to the present invention has a solubilityof 15 to 20 μg/mL in a 1 wt % methylcellulose solution at 37° C.

Amorphous compound A according to the present invention can be producedby dissolving compound A in methylene chloride and then spray drying thesolution.

Crystalline compound A is hardly soluble in water as well as in variousgeneral-purpose solvents, and the solubility of crystalline compound Ain methylene chloride is as low as about 1% by weight. However, oncecrystalline compound A is dissolved in methylene chloride, compound A isnot precipitated as a crystal even when the solution is concentrated toa compound A concentration exceeding 15% by weight. Further, regardlessof whether or not the concentration procedure is carried out, amorphouscompound A can be provided by spray drying the solution of compound A inmethylene chloride. Setting the concentration of the solution used forspray drying at a high value is preferred for spray dried productrecovery efficiency enhancement purposes or spray drying treatment timeshortening purposes. Accordingly, in a preferred embodiment of thepresent invention, after the concentration procedure, the solution ofcompound A in methylene chloride is spray dried. The concentration ofcompound A in the methylene chloride solution to be spray dried ispreferably in the range of 1 to 15% by weight, more preferably in therange of 3 to 10% by weight. Details of spray drying and specificmethods for spray drying will be described later.

Amorphous compound A according to the present invention exhibitsimproved solubility particularly in water over crystalline compound Aand thus is preferably used as a pharmaceutical bulk, especially as apharmaceutical bulk for the production of a pharmaceutical compositionfor oral administration. Compound A can be used for prophylaxis ortherapy of allergic diseases. Allergic diseases include, for example,bronchial asthma, eczema, hives, allergic gastrointestinal injury,allergic rhinitis, and allergic conjunctivitis.

Amorphous compound A according to the present invention as such may beadministered orally. In general, however, amorphous compound A accordingto the present invention, together with a conventional pharmaceuticallyacceptable carrier, is formulated into oral preparations. Amorphouscompound A according to the present invention can be formulated, byusing, as carriers, excipients (for example, lactose, crystallinecellulose, starch, and calcium hydrogenphosphate), binders (for example,starch, carmellose sodium, and hydroxypropylcellulose), disintegrants(for example, carmellose calcium, croscarmellose sodium), lubricants(for example, magnesium stearate and talc) and the like, into dosageforms commonly supplied in medical fields, that is, tablets, capsules,granules, dry syrup, and various liquid preparations including syrupprepared by a conventional method. Further, these various preparationsmay be in a sustained release form which has persistent effect for along period of time.

According to another aspect of the present invention, there is provideda method for preventing or treating an allergic disease, said methodcomprising the step of administering amorphous compound A according tothe present invention to an animal including a human. Further, accordingto a further aspect of the present invention, there is provided use ofamorphous compound A according to the present invention, for theproduction of an antiallergic agent.

Composition Comprising Amorphous Compound A

According to the present invention, there is provided a composition,especially a pharmaceutical composition, comprising amorphous compoundA. In a preferred embodiment of the present invention, there is provideda pharmaceutical composition particularly for oral administration.

In a preferred embodiment of the present invention, amorphous compound Aaccording to the present invention, together with methylcellulose orhydroxypropylmethylcellulose, is formulated in the composition. CompoundA contained in this composition can maintain good solubility in solventssuch as water for a long period of time. While there is no intention ofbeing bound by the following theory, it is believed that methylcelluloseand hydroxypropylmethylcellulose can suppress the crystallization ofamorphatized compound A to maintain good solubility of amorphouscompound A for a long period of time. Even when the amount ofmethylcellulose and hydroxypropylmethylcellulose formulated is small,unexpectedly, the effect of maintaining compound A in an amorphous stateis good. In a more preferred embodiment of the present invention,however, when the amount of amorphous compound A is presumed to be 1,the mixing ratio (on a weight basis) to the total amount ofmethylcellulose and hydroxypropylmethylcellulose is preferably in therange of 0.01 to 2. The lower limit of the mixing ratio is morepreferably 0.05, and the upper limit of the mixing ratio is morepreferably 1.

In another aspect of the present invention, there is providedcomposition comprising amorphous compound A according to the presentinvention and a polymeric compound the formulation of which is generallypharmaceutically acceptable. The polymeric compound may be selected fromthe group consisting of ethylcellulose, hydroxypropylmethylcellulosephthalate, hydroxypropylcellulose, carboxymethylethylcellulose,polyvinyl pyrrolidone, polyvinyl acetal diethylaminoacetate, methacrylicacid copolymer L, aminoalkyl methacryl acrylate copolymer E, and vinylacetate-vinylpyrrolidone copolymer. These polymeric compounds may beused as a mixture of two or more.

The composition according to the present invention can be produced bypreparing amorphous compound A and then physically mixing amorphouscompound A with methylcellulose or hydroxypropylmethylcellulose or apolymeric compound.

In another embodiment of the present invention, the compositionaccording to the present invention can be produced by dissolving bothcompound A and methylcellulose or hydroxypropylmethylcellulose or apolymeric compound in methylene chloride and then spray drying thesolution.

When only methylene chloride is used, some of polymeric compounds arenot dissolved or are low in dissolution rate. For example,methylcellulose, hydroxypropylmethylcellulose,hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, andmethacrylic acid copolymer L have this tendency. When such polymericcompounds are used, the use of a mixed solvent prepared by adding alower alcohol such as methanol or ethanol to methylene chloride cansolve this problem and can realize the dissolution thereof. In apreferred embodiment of the present invention, the lower alcohol is analkyl alcohol having 1 to 3 carbon atoms.

In a preferred embodiment of the present invention, the composition isproduced by dissolving crystalline compound A in methylene chloride toprepare a solution, then optionally concentrating the solution, adding alower alcohol to the solution or the concentrate to prepare a mixedsolution, dissolving the above polymeric compound in the mixed solutionto prepare a solution, and spray drying the solution, or by mixing asolution of compound A in methylene chloride with a separately preparedsolution or suspension of the above polymeric compound in a loweralcohol, stirring the mixture to prepare a solution, and spray dryingthe solution.

The mixing ratio between methylene chloride and lower alcohol is notparticularly limited so far as the mixture, together with compound A andmethylcellulose or hydroxypropylmethylcellulose or a polymeric compound,can form a solution. The weight ratio of the lower alcohol to methylenechloride, however, is preferably such that the amount of the loweralcohol is not more than three times, more preferably not more than 1.5times, the amount of methylene chloride.

The composition according to the present invention thus obtained as suchmay be administered orally. In general, however, the compositionaccording to the present invention, together with a conventionalpharmaceutically acceptable carrier, is formulated into oralpreparations. Carriers usable herein include those as described above inconnection with amorphous compound A.

Further, according to another aspect of the present invention, there isprovided a method for preventing or treating an allergic disease, saidmethod comprising the step of administering the composition according tothe present invention comprising amorphous compound A to an animalincluding a human. According to a further aspect of the presentinvention, there is provided use of the pharmaceutical compositionaccording to the present invention comprising amorphous compound A, forthe production of an antiallergic agent.

Spray Drying

In the present invention, spray drying may be carried out in the sameapparatus as commonly used in fields such as food products,pharmaceutical products, and various chemical industries. When a loweralcohol is added to the solution to be spray dried, however, the use ofan explosion-proof type spray dryer is preferred.

When the time required from mist formation to drying in the step ofspray drying is long, disadvantageously, there is a significant tendencyof the presence of crystalline compound A and amorphous compound A as amixture. In order to provide the amorphous compound free from thecrystalline compound, minimizing the diameter of the spray mist ispreferred. To this end, in addition to the following operatingconditions of the spray dryer, the specifications and capacity of asolution spray device are also important. The spray device is preferablya two fluid nozzle or a four fluid nozzle rather than a rotary atomizer.Since, however, which device is to be used also depends upon operationconditions, the spray device is not necessarily limited to the two fluidnozzle and four fluid nozzle.

In spray drying, as described above, since the spray mist diameter isreduced, the particle diameter of the spray dried product is alsoreduced. In addition to cyclone commonly used in the art, variousfilters may be used for collection of the spray dried product.

Regarding operating conditions for the spray dryer, in supply of gasinto a drying chamber, when the solvent is methylene chloride, gases,commonly used in spray drying, including compressed air may be used.When the solvent is a mixed solvent composed of methylene chloride and alower alcohol, an explosion-preventive oxygen-free gas such as nitrogengas is used. Supply gas temperature is preferably in the range of 40 to120° C., more preferably in the range of 50 to 100° C. When mist isformed using a spray nozzle, the supply gas pressure is preferably inthe range of 0.05 to 1.5 MPa and more preferably in the range of 0.1 to0.7 MPa from the viewpoint of reducing the spray mist diameter asdescribed above. The feed speed of the solution containing compound A isnot particularly limited, because it may vary depending upon adifference in spray mist formation method, supply gas pressure, and thesize of the spray dryer.

EXAMPLES

The present invention is further illustrated by the following Examplesthat are not intended as a limitation of the invention.

In the following Examples and Comparative Examples, a powder X-raydiffraction apparatus was used for evaluation under the followingmeasuring conditions.

Apparatus: RINT 2200 (manufactured by Rigaku Industrial Corporation)

Measuring conditions: lamp; Cu, tube voltage; 40 kV, tube current; 20mA, monochromator; graphite, scanning speed; 4°/min, scanning step;0.02°, scanning axis; 2 θ/θ, divergent slit; 1°, scattering slit; 1°,light receiving slit; 0.30 mm, scanning range; 3 to 40°

Comparative Example 1

A light yellow powder produced according to the method described inExample 20 of WO 99/16770 was dissolved in methylene chloride to preparea solution which was then recrystallized from methanol to givecrystalline compound A. The crystalline compound A exhibitedcharacteristic diffraction peaks as analyzed by powder X-raydiffractometry.

Example 1

The crystalline compound A (30 g) produced in Comparative Example 1 wasdissolved in 2000 g of methylene chloride to prepare a solution whichwas then concentrated under the reduced pressure to give a 5 wt %solution. The concentrated solution was treated in a spray drier (ModelGS 31, manufactured by YAMATO SCIENTIFIC CO., LTD.) (air feed temp.: 70°C., liquid feed rate: 10 g of solution per min) to give 23 g of a lightyellow amorphous powder. The powder did not exhibit any characteristicdiffraction peak as analyzed by powder X-ray diffractometry.

Example 2

The crystalline compound A (360 g) produced in Comparative Example 1 wasdissolved in 2600 g of methylene chloride to prepare a solution whichwas then concentrated under the reduced pressure to give a 8 wt %concentrated solution. The concentrated solution was mixed with asolution of 72 g of methylcellulose (Metlose SM15, manufactured by TheShin-Etsu Chemical Co., Ltd.) in 2700 g of methanol. The mixed solutionwas treated in a spray drier (Model CL-8, manufactured by OhkawaraKakohki Co., Ltd.) (air feed temp.: 90° C., liquid feed rate: 20 g ofsolution per min) to give 290 g of a light yellow powder. The powder didnot exhibit any characteristic diffraction peak as analyzed by powderX-ray diffractometry.

Example 3

The crystalline compound A (20 g) produced in Comparative Example 1 wasdissolved in 1400 g of methylene chloride to prepare a solution whichwas then concentrated under the reduced pressure to give a 4 wt %concentrated solution. Methanol (320 g) was added to the concentratedsolution, and 4 g of hydroxypropylmethylcellulose (TC-5R, manufacturedby The Shin-Etsu Chemical Co., Ltd.) was further added and dissolvedtherein to prepare a solution. The solution was treated in a spray drier(Model GS 31) (air feed temp.: 90° C., liquid feed rate: 10 g ofsolution per min) to give 13 g of a light yellow powder. The powder didnot exhibit any characteristic diffraction peak as analyzed by powderX-ray diffractometry.

Example 4

The crystalline compound A (8 g) produced in Comparative Example 1 wasdissolved in 560 g of methylene chloride to prepare a solution which wasthen concentrated under the reduced pressure to give a 4 wt %concentrated solution. Methanol (120 g) was added to the concentratedsolution, and 1.6 g of methylcellulose (Metlose SM 15) and 1.6 g ofhydroxypropylmethylcellulose (TC-5R) were further added and dissolvedtherein to prepare a solution. The solution was treated in a spray drier(Model GS 31) (air feed temp.: 90° C., liquid feed rate: 10 g ofsolution per min) to give 7 g of a light yellow powder. The powder didnot exhibit any characteristic diffraction peak as analyzed by powderX-ray diffractometry.

Examples 5 to 13

In Examples 5 to 13, compounds were produced in the same manner asdescribed above, except that only the polymer compound was changed.

Specifically, crystalline compound A (8 g) produced in ComparativeExample 1 was dissolved in 560 g of methylene chloride to prepare asolution which was then concentrated under the reduced pressure to givea 4 wt % concentrated solution. Methanol (120 g) was added to theconcentrated solution, and 1.6 g of the following polymer compound wasfurther added and dissolved therein.

Example 5: Ethylcellulose (Shin-Etsu ethylcellulose, manufactured by TheShin-Etsu Chemical Co., Ltd.)

Example 6: Hydroxypropylmethylcellulose phthalate (HPMCP, manufacturedby The Shin-Etsu Chemical Co., Ltd.)

Example 7: Hydroxypropylcellulose (NISSO-HPC-L, manufactured by NipponSoda Co., Ltd.)

Example 8: Carboxymethylethylcellulose (CMEC, manufactured by FreundIndustrial Co., Ltd.)

Example 9: Polyvinyl pyrrolidone (Kollidon K30, manufactured by BasfJapan)

Example 10: Polyvinyl acetal diethylaminoacetate (AEA SANKYO,manufactured by SANKYO CO., LTD.)

Example 11: Methacrylic acid copolymer L (Eudragit L, manufactured byRoehm Pharma)

Example 12: Aminoalkyl methacryl acrylate copolymer E (Eudragit E,manufactured by Roehm Pharma)

Example 13: Vinyl acetate-vinylpyrrolidone copolymer (Plasdone S-630,manufactured by ISP)

The solutions thus obtained were treated in a spray drier (Model GS 31)(air feed temp.: 90° C., liquid feed rate: 10 g of solution per min) togive light yellow powders. All the powders did not exhibit anycharacteristic diffraction peak as analyzed by powder X-raydiffractometry.

Example 14

Amorphous compound (10.0 g) produced in Example 1, mannitol (10.0 g),hydroxypropylmethylcellulose (2.0 g), sodium carboxymethyl starch (5.0g), and magnesium stearate (0.135 g) were mixed together, and themixture was tabletted (tabletting pressure: 2 tons/tablet) by a rotarytablet machine. The tablets were disintegrated with mortar/pestle,followed by particle size regulation with a sieve (No. JP 30). Sodiumcarboxymethyl starch (10.0 g) was added to and mixed with the granulesthus obtained, and 371.35 mg of the mixture was filled into ahydroxypropylmethylcellulose capsule (No. 0) to prepare a capsulepreparation containing 100 mg of the amorphous compound produced inExample 1 per preparation.

Test Example 1 Powder X-Ray Diffraction

The powders produced in Examples 1 and 2 and crystalline compound Aproduced in Comparative Example 1 were tested for crystallinity (degreeof crystallization). The results were as shown in FIG. 1.

Crystalline compound A produced in Comparative Example 1 exhibitedcharacteristic diffraction peaks attributable to regular spacialconfiguration of the molecule constituting a crystal lattice as analyzedby powder X-ray diffractometry. On the other hand, none of the amorphouscompound produced in Example 1 and the amorphous composition produced inExample 2 according to the present invention exhibits any characteristicdiffraction peak as analyzed by powder X-ray diffractometry. The sameresults were obtained for the composition produced in Examples 3 to 13.These facts demonstrate that all of the amorphous compound and amorphouscompositions of the examples of the present invention are amorphous.

Test Example 2 Dissoluvability Test (1)

Water or a 1 wt % aqueous methylcellulose solution was provided as atest liquid, and solubility of various samples in the test liquid wasexamined. Each sample in an amount of about 100 mg in terms of compoundA was added to 500 mL of the test liquid kept at 37° C., and the mixturewas stirred with a paddle at 200 rpm. Sampling was carried out atpredetermined time intervals, and the samples were filtered through amembrane filter (Sumplep LCR 13-LG, manufactured by MilliporeCorporation). The concentration of compound A in each of the filtrateswas analyzed by HPLC. The results are shown in FIGS. 2 and 3.

In Test Example 2, HPLC was carried out under the following measuringconditions.

Detector: Ultraviolet absorptiometer (measuring wavelength: 240 nm)

Column: Inertsil ODS 2 4.6×250 mm in which a stainless tube having aninner diameter of 4.6 mm and a length of 25 cm was packed with a 5-μmoctadecylsilyl silica gel for liquid chromatography.

Column temp.: Around 40° C.

Mobile phase: 0.1 wt % ammonium acetate:methanol (45:55)

Flow rate: 1 mL/min

When the test liquid was water (FIG. 2), the concentration ofdissolution of crystalline compound A produced in Comparative Example 1in this system was not more than 1 μg/mL. For the powders (amorphouscompositions) produced in Examples 2 and 3, the concentration ofdissolution was about 18 μg/mL, and this concentration was maintainedfor 4 hr. For the amorphous compound produced in Example 1, theconcentration of dissolution reached about 5 μg/mL and then lowered toabout 3 μg/mL. This lowering in concentration is considered attributableto crystallization of the amorphous compound in water. On the otherhand, when the test liquid was the 1 wt % aqueous methylcellulosesolution (FIG. 3), the concentration of dissolution of crystallinecompound A produced in Comparative Example 1 was not more than 1 μg/mLas with the case where the test liquid was water, whereas theconcentration of dissolution of the amorphous compound produced inExample 1 was not less than about 18 μg/mL and this concentration wasmaintained for 4 hr. From these results, it appears that methylcellulosesuppresses crystallization of the amorphous compound produced in Example1 rather than contribution to the solubilization of crystalline compoundA.

Test Example 3 Dissoluvability Test (2)

Water was provided as a test liquid, and the dissolution of the capsulepreparation produced in Example 14 was examined with an elution tester(model NT-6100 manufactured by TOYAMA SANGYO Co., Ltd., automaticmeasurement by ultraviolet absorptiometry, detection wavelength: 246nm). Specifically, the capsule preparation produced in Example 14(containing 100 mg of amorphous compound A produced in Example 1) wasadded to 900 mL of water (37° C.), followed by stirring with a paddle at100 rpm. The results were as shown in FIG. 4.

For the amorphous compound produced in Example 1, the concentration ofdissolution in water was rapidly lowered (FIG. 2), while the lowering inconcentration of dissolution did not occur in an aqueous methylcellulosesolution (FIG. 3). This dissolution was the same as the dissolution ofthe amorphous compositions produced in Examples 2 and 3. From the aboveresults, it is considered that methylcellulose and/orhydroxypropylmethylcellulose may be formulated as an ingredient in theproduction of a preparation using the amorphous compound.

As a result of the dissoluvability test, carried out in water, of thecapsule preparation produced in Example 14 while taking the above factinto consideration (FIG. 4), it was found that the amorphous compoundproduced in Example 1 formulated into the capsule preparation did notcause a rapid lowering in concentration of dissolution as shown in FIG.2. These results show that the amorphous compound produced in Example 1is also useful as a raw material of a pharmaceutical preparation andthat the dissolution of the amorphous compound can be maintained byseparately formulating methylcellulose and/orhydroxpropylmethylcellulose as a pharmaceutical additive.

Test Example 4 Absorption Test

Compound A, when absorbed in the living body, is converted to asubstance, which develops its physiological activity, that is,7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine (WO95/18130; hereinafter referred to as “compound B”).

The sample produced in Comparative Example 1 or Example 1 was suspendedin a 1 wt % aqueous methylcellulose solution. The suspension wasadministered orally to beagles (n=6) which had been subjected to fastingovernight. As a result, the compound B concentration of plasma over timewas as shown in FIG. 5. The difference in absorption among the sampleswas evaluated by comparing the area under the plasma drugconcentration-time curve (AUC).

The plasma drug concentration in the collected blood was quantitativelydetermined according roughly to the following method.

Blood (about 0.7 mL) collected from the cephalic vein was centrifuged(4° C., about 9000×g, 10 min) in the presence of heparin to obtainplasma. Methanol (400 μL) and an internal standard substance solution(sodium salt of7-methyl-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, 100ng/mL, 100 μL) were added to the plasma (100 μL), and the mixture wasstirred and centrifuged (4° C., about 9000×g, 10 min).

The supernatant was evaporated to dryness at room temperature under anitrogen gas stream, and 150 μL of a mixed solution composed of a 10mmol/L phosphate buffer (pH 7.0) and a methanol (8:2) was added to theresidue for redissolution. The solution was then filtered by acentrifugal filter (Centricut Ultra-Mmini (KURABO INDUSTRIES LTD.), 4°C., about 9000×g, 10 min), and the filtrate was analyzed as a sample byHPLC. In this Test Example 4, HPLC was carried out under the followingmeasuring conditions.

HPLC pump: PU-980 (Japan Spectroscopic Co., Ltd.)

Degassor: DG-980-50 (Showa Denko K.K.)

Autosampler: AS-950-10 (Japan Spectroscopic Co., Ltd.)

Detector: FP-920 (Japan Spectroscopic Co., Ltd.)

Fluorescence detection wavelength: Ex 270 nm, Em 466 nm (GAIN=100,response=standard)

Column: CAPCELLPAC C18 UG 120 (4.6×250 mm, 5 μm, Shiseido Co, Ltd.)

Column temp.: 40° C.

Mobile phase: Linear gradient using 10 mmol/L phosphate buffer (pH 7.0)and methanol (8:2→2:8)

Flow rate: 1.0 mL/min

Injection volume: 20 μL

As compared with oral administration of the crystalline compoundproduced in Comparative Example 1, the plasma compound B concentrationafter the administration of the amorphous compound produced in Example 1was significantly higher. Further, even when the amorphous compoundproduced in Example 1 was administered at a dose which is one-eighth ofthe dose of the crystalline compound produced in Comparative Example 1,in a change in the plasma compound B concentration over time, the plasmacompound B concentration in the case of the administration of theamorphous compound produced in Example 1 was much higher than the plasmacompound B concentration in an animal group to which the crystallinecompound produced in Comparative Example 1 had been administered. Thesefacts demonstrate that the amorphous compound produced by the presentinvention had significantly improved absorption. The same results wereobtained when cynomolgus monkeys were used.

1. A composition comprising an amorphous compound2-(1-isopropoxy-carbonyloxy-2-methylpropyl)-7, 8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine having no diffractionpeak in a powder X-ray diffraction pattern and a solubility of 15 to 20μg/mL in a 1 wt % methylcellulose solution at 37° C. and methylcelluloseand/or hydroxypropylmethylcellulose.
 2. The composition according toclaim 1, wherein the mixing ratio of the amorphous compound of2-(1-isopropoxy-carbonyloxy-2-methylpropyl )-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine to the total amount ofmethylcellulose and/or hydroxypropylmethylcellulose is in the range of1:0.01 to
 2. 3. A composition comprising2-(1-isopropoxy-carbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine having no diffractionpeak in a powder X-ray diffraction pattern and a solubility of 15 to 20μg/mL in a 1 wt % methylcellulose solution at 37° C. and a polymercompound, wherein the polymer compound is one or at least two compoundsselected from the group consisting of ethylcellulose,hydroxypropylmethylcellulose phthalate, hydroxypropylcellulose,carboxymethylethylcellulose, polyvinyl pyrrolidone, polyvinyl acetaldiethylaminoacetate, methacrylic acid copolymer L, aminoalkyl methacrylacrylate copolymer E, and vinyl acetate-vinylpyrrolidone copolymer.
 4. Aprocess for producing the composition according to claim 1, said processcomprising the steps of: dissolving 2-(1-isopropoxycarbonyloxy-2-methylpropyl )-7,8-dimethoxy-4(5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine and methylcellulose and/orhydroxypropylmethylcellulose in methylene chloride to prepare asolution; and then spray-drying the solution.
 5. A process for producingthe composition according to claim 3, said process comprising the stepsof: dissolving2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4(5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine and the polymer compoundin methylene chloride or a methylene chloride/lower alcohol mixedsolvent to prepare a solution; and then spray-drying the solution. 6.The process according to claim 5, wherein the lower alcohol is an alkylalcohol having 1 to 3 carbon atoms.
 7. A pharmaceutical composition fororal administration, comprising the composition according to claim 1 anda pharmaceutically acceptable carrier.
 8. A pharmaceutical compositionfor oral administration, comprising the composition according to claim 2and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition for oral administration, comprising the compositionaccording to claim 3 and a pharmaceutically acceptable carrier.
 10. Amethod for treating an allergic disease, wherein said method comprisesthe step of administering the composition according to claim 1 to ananimal.
 11. A method for treating an allergic disease, wherein saidmethod comprises the step of administering the composition according toclaim 2 to an animal.
 12. A method for treating an allergic disease,wherein said method comprises the step of administering the compositionaccording to claim 3 to an animal.
 13. The method of any one of claims10-12 wherein said animal is a human.